Changing clinical manifestations of dengue infection in north India

Transcription

1 Changing clinical manifestations of dengue infection in north India Chandrakanta, Rashmi Kumar #, Garima, Jyotsana Agarwal, Amita Jain, Rachna Nagar Departments of Paediatrics and Microbiology, Chhatrapati Shahuji Maharaj Medical University (CSMMU), Lucknow , India Abstract Dengue infection is endemic in many parts of India, including the state of Uttar Pradesh. This study describes the changing clinical picture of dengue viral infections observed by us in children admitted to a teaching hospital in Lucknow, India. A total of 139 children with suspected dengue were admitted during this period, of which 124 could be tested by dengue IgM capture ELISA and 102 were positive. However, only 80 of these 102 patients could be followed up. Average age was 5.9 (±3.1) years and 87.5% of them were from rural areas. The male:female ratio was 1.6:1. Seizures were observed in 45% cases, altered sensorium in 53.7%, vomiting in 41.2%, haemorrhage in 38.8%, skin rash in 37.5%, abdominal pain in 25%, headache in 18.8% and jaundice in 2% cases. Gastrointestinal tract was the commonest site of bleeding. On examination, edema was present in 47.5% cases, hepatomegaly in 62.5%, splenomegaly in 60.0% and hypotension in 10.0% cases. The investigations revealed a low platelet count of less than /mm 3 in 60.3% cases. Mean liver enzyme levels were mildly raised. Definitions of WHO criteria for DHF were present in only 18 (22.5%) cases. Mean total duration of fever in survivors was 14.9±7.3 days. The overall fatality rate in hospital was 5.0%. The results indicated a significant proportion of children presented with little-described features of encephalopathy, edema, splenomegaly and prolonged fever rather than the typical dengue presentation. These features were not noted during the past epidemics and in previous years. Keywords: Dengue viral infection; Dengue fever; Dengue encephalopathy; Dengue haemorrhagic fever. Introduction Dengue infection is the most important arbovirus infection of humans and the most important tropical infectious disease after malaria. Although dengue fever is a very old disease, more complicated forms of the infection dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS) have been recognized in the last century [1]. In India, the # rashmik2005@gmail.com 118 Dengue Bulletin Volume 32, 2008

2 first virologically confirmed epidemic occurred in Calcutta (now known as Kolkata) and the eastern coast of India in [2]. All four serotypes of the virus are circulating now [3]. A major widespread epidemic of DHF occurred in 1996 involving areas around Delhi, and, since then, there has been a remarkable resurgence of the infection in north Indian plains that include the state of Uttar Pradesh. Once considered an urban problem, it has now penetrated into rural areas also due to high population density and other factors [4]. As observed in this part of the country, dengue infection is showing an increasing trend. The illness occurs throughout the year with a peak during monsoon and post-monsoon season due to high vector density. Major outbreaks have occurred in this region in 2003 and Besides the increasing frequency of the infection, even the manifestations observed have been varied. In 2008, we observed manifestations of dengue which were not commonly observed in the previous years. We, therefore, undertook to prospectively study and describe the varied manifestations of dengue viral infection as seen in hospitalized children in northern India. Materials and methods This study was conducted in the Department of Paediatrics of Chhatrapati Shahuji Maharaj Medical University (CSMMU) Hospital, Lucknow a tertiary-care teaching hospital. Over a period of five months from August to December 2008, we carefully screened admissions for suspected diagnosis of dengue, as made by the admitting physician, usually on the basis of febrile illness with rash, or bleeding with or without alteration of consciousness. A detailed clinical history was taken, physical examination was performed and baseline investigations were noted using a structured proforma. Laboratory investigations and treatment of the patients were decided by the treating physician. Tests that were usually done included haemoglobin (Hb), total and differential leukocyte count (TLC and DLC), platelet count (PLT count), haematocrit (HCT), and liver function tests (LFT) including prothrombin time (PT), serum proteins and albumin. Lumbar puncture and cerebrospinal fluid (CSF) examination was usually done in patients who presented with a history of altered sensorium and/or seizures. Serology for dengue infection was also done as part of routine clinical work. Blood samples were collected and transported to the Department of Microbiology, CSMMU. They were tested for dengue IgM by antibody capture ELISA (Mac ELISA) test using commercial kits marketed by IVD Research Inc., USA. Thus, the study was purely observational. Diagnosis of dengue infection, DF and DHF was made according to WHO criteria [5]. If altered sensorium was present, the child was classified as dengue encephalopathy (DE) with or without DHF. Statistical analysis Data were entered into a Microsoft Excel sheet. Frequencies, mean and standard deviation was calculated by using Epi-info software for statistical analysis. Results During the period of the study, a total of 139 suspected dengue patients were admitted to the hospital, of which 124 could be tested for dengue IgM, and 102 were positive. Of these 102 patients, 80 could be followed up and documented. The clinical features of these 80 patients are given in Table 1. Dengue Bulletin Volume 32,

3 Table 1: Clinical features of dengue IgM-positive cases S. Clinical features Dengue IgM +ve cases No. (n=80) No (%) 1. Mean age in years ± SD 5.9± Male:Female ratio 1.6:1 3. Residence in rural area 70 (87.5) 4. Fever 80 (100) 5. Average duration of fever at admission in days ± SD 10.7± Altered sensorium 43 (53.7) 7. Seizures 36 (45) 8. Abdominal pain 20 (25) 9. Haemorrhage 31 (38.8) 10. Diarrhoea 5 (6.2) 11. Vomiting 33 (41.2) 12. Headache 15 (18.8) 13. Rash 30 (37.5) 14. Edema 38 (47.5) 15. Hepatomegaly 50 (62.5) 16. Splenomegaly 48 (60.0) 17. Hypotension 8 (10.0) 18. Meningeal signs 7 (8.7) 19. Raised intracranial tension (ICT) 5 (6.2) 20. Jaundice 2 (2.5) 21. Total duration of fever in days ± SD 14.9± DHF 18 (22.5) DE 43 (53.7) DE+DHF 7 (8.7) 23. Duration of hospital stay in days ± SD 7.6± Mortality in hospital 4 (5.0) In the 80 serologically-confirmed cases, 18 (22.5%) satisfied WHO criteria for DHF, while 43 (53.7%) had encephalopathy. Seven patients with DHF had encephalopathy also. One case with clinical presentation of Guillian Barré syndrome was also dengue IgM-positive. Mean duration of fever at presentation was 10.7±6.2 days. After follow-up, mean total duration of fever in survivors was found to be 14.9±7.3 days. Other main complaints besides fever were: swelling over body, rash, altered sensorium, seizures, vomiting, bleeding, abdominal pain and headache. On examination, a discrete maculopapular erythematous rash was present in 37.5% cases. Edema was present in 47.5% children. It was generalized in 36.3%, over extremities in 6.2% and facial in 5% children. Haemorrhage was found in 31 (38.8%) children. Gastrointestinal tract was the most common site for bleeding (23.7%) followed by the skin (16.2%). 120 Dengue Bulletin Volume 32, 2008

4 Conjunctival haemorrhage and epistaxis were noted in 2 patients (4.1%) and 1 patient (2.0%) respectively. Intracranial haemorrhage was suspected in one child, but cranial imaging could not be done in this case. One child developed haemorrhagic pleural effusion and another had pulmonary haemorrhage. Gum bleeding was not present in any child. Hepatomegaly and splenomegaly were present in 62.5% and 60% cases respectively. Mean liver size was 4.1±1.1 cm below costal margin and mean spleen size was 2.8±1.4 cm below costal margin at the time of admission. Seizures occurred in 36 (45%) of cases. Altered sensorium was present on admission in 41 (51.2%). In children with altered sensorium, rash was seen in 18 (43.9%), bleeding manifestations were seen in 15 (38.5%) and swelling in 13 (31.7%). Alteration of sensorium developed later in another 2 patients. The average duration of altered consciousness on admission was 2.8±5.2 days and for seizures 2.8±5.3 days. Generalised hypertonia was found in 21 (48.8%) subjects with encephalopathy, meningeal signs in 7 (16.8%) and focal neurological deficit in 2 Table 2: Laboratory investigations in dengue IgM-positive cases S. Investigation Dengue IgM +ve cases No. (n=80) No (%) 1. Mean Hb (gm%) ± SD 9.8± Mean total leukocyte count (per mm3) ± SD 9848± Mean % polymorphs in blood 61.5± Platelet count (per mm3) in blood < (13.7) (16.2) (13.7) (11.2) (6.2) > (40.0) 5. Mean packed cell volume (PCV) (%) ± SD 26.8± Mean serum bilirubin (in mg%) ± SD 1.0± Mean sgot (IU) ± SD sgot(iu) >40 IU 98.4±69.820/26 (76.9) 8. Mean SGPT (IU) ± SD sgpt(iu)> 40 IU 78.1±66.422/33 (66.7) 9. Mean International Normalized Ratio (INR) ± SD 1.8± Mean serum sodium (in meq/l) ± SD 132.5± Mean urea (in mg%) ± SD 35.0± Mean serum protein (in gm%) ± SD <6.1 gm% 5.9±0.814/26 (53.8) 13. Mean serum albumin (in gm%) ± SD 3.1± CSF findings (38 patients) CSF pleocytosis (>10 cells/mm 3 ) 17/38 (44.7) 30.4±80.6 Mean cell count ± SD (per mm 3 ) 11.9±24.2 Mean polymorphs% ± SD Mean CSF protein (in mg%) ± SD 84.4±61.1 CSF sugar normal (>=2/3 rd of blood sugar) 29 (80.6) CSF sugar decreased (<2/3 rd of blood sugar) 7 (19.4) Dengue Bulletin Volume 32,

5 (4.6%) children. Five (6.2%) patients developed features of raised intracranial tension (ICT) such as hypertension, bradycardia and hyperventilation. The laboratory findings are given in Table 2. The platelet count was below /mm 3 in 48 (60%) cases. In 13.7% cases the platelet count was below mm 3. Liver enzymes sgot and sgpt were raised above the normal limit in 76.9% and 66.7% cases respectively. Packed cell volume was greater than 36 in 2 patients only. Examination of the cerebrospinal fluid was done in 38 patients, of which 17 (44.7%) showed pleocytosis with mean cell count of 30.4±80.6/mm 3. Mean CSF protein was 84.4±61.1 mg%. Discussion Dengue is a major public health problem in Lucknow and surrounding districts in the state of Uttar Pradesh in north India. Over the last 7 8 years we have been observing varied clinical manifestations of dengue, which are rather different from the past reports from this region as well as from other parts of the country. An encephalopathic presentation was noted by us from 2003 itself, which led us to test consecutive children hospitalized with acute febrile encephalopathy (AFE) for dengue IgM and genome in CSF and serum. Of a total of 265 patients of AFE tested, 39 (14.7%) were conclusively proven to have dengue viral infection [6]. We also observed dengue viral infection presenting as acute hepatic failure. A total of 27 children admitted with acute hepatic failure were tested for dengue IgM of which 13 were unequivocally positive, and 7 of these were tested for dengue genome by RT-PCR, of which 4 were positive [7]. In 298 patients of acute undifferentiated febrile illness, dengue IgM was positive in 56 (18.8%) and dengue genome was detected in 15 of 44 IgM-positive cases [8]. It was observed that in addition to the well-known WHO criteria for case definition of DF, altered liver function with moderate elevation of transaminases is a differentiating feature of dengue. Over the last two seasons we have observed a further shift in the clinical manifestations, which we think is worthy of dissemination through this communication. Our patients did not include all dengue IgM-positive cases over the study period. However, they were unselected cases and therefore unlikely to represent a biased group. Most of the dengue cases belonged to rural areas. This may only reflect the predominantly rural population admitted to this hospital. In two studies conducted between 2003 and 2006 we found no significant difference in the incidence between rural and urban areas [4]. The major difference from the previous reports is the frequent occurrence of encephalopathy, swelling, splenomegaly and prolonged fever. Encephalopathy, an important manifestation of dengue infection seen here, has been reported by us previously. It was observed in 53.7% patients in this series, but was not reported by earlier workers from Lucknow [9,10] and was seen in only 4% cases in the Delhi epidemic of 1996 [11]. Rash, swelling and/or bleeding manifestations in these patients are suggestive of dengue and prompts testing for dengue IgM. Encephalopathy has been reported in several studies from Thailand [12-16]. Encephalopathy in dengue was believed to be due to cerebral edema, hyponatremia, hypoperfusion or intracranial bleed, but, more recently, the actual dengue viral invasion of the brain is recognized [17,18]. Another manifestation observed by us frequently over the last few years is the presence of swelling which was found in almost 122 Dengue Bulletin Volume 32, 2008

6 Figure: Characteristic swelling on the face of a child with dengue encephalopathy half of our patients (Figure). This is a peculiar generalized non-pitting edema which may be explained by plasma leak in DHF. However, no earlier workers from India or abroad have mentioned this finding. Only 15 of the patients with swelling had received intravenous fluids prior to presentation here. Swelling was not seen in patients with other diagnoses seen here even if fluids had been administered outside. Although hepatomegaly is among the WHO clinical criteria for DF, splenomegaly is not generally held to be a feature of dengue infection. Earlier reports from Lucknow [9,10] and other parts of India [11,19-21] do not describe a high frequency of splenomegaly. In our earlier studies we too did not usually find splenomegaly in DF, DHF or DE [6-8]. However, in this season (2008), it was observed commonly in almost 3/5 th of the cases. Peripheral smears for malaria were negative in all cases. A recent study from Delhi has reported a somewhat high percentage (32.4%) of splenomegaly in children with dengue [22]. Dengue fever is generally described as a short febrile illness. The WHO criteria mention an illness of 2 7 days duration [5]. Over the last two years we have observed a longer duration of fever than in previous years. The mean duration of fever in survivors in this study was almost 15 days. On an analysis of the laboratory findings, it was observed that platelets were below /mm 3 in a majority of the cases, with roughly 1/6 th having counts below / mm 3. Liver transaminases showed a mild-tomoderate elevation in around 3/4 th patients. Alterations in liver functions are well-known in dengue infection [23-26], but are not listed in the WHO criteria for case definition [5]. Packed cell volumes (PCV) were almost always low in our patients, presumably due to high prevalence of anaemia. The diagnosis of DHF rests heavily on finding a high PCV, but in our patients, we have to rely on other evidences of capillary leak like low serum proteins. Even this may be misleading because serum proteins may be low due to malnutrition also. Demonstration of pleural fluid or ascites is difficult because these findings may not be found in all stages of the illness and involves transportation of a sick child. Therefore, only about a fourth of our hospitalized patients had definite WHO features for case definition of DHF. We strongly feel that these case definitions need revision as these cannot be applied in settings such as ours where dengue regularly occurs. Our study patients had a severe presentation and rather high mortality. This is because all were hospitalized patients. If all dengue cases occurring in the community were to be described then we expect the severe manifestations and mortality to be certainly lower. However, such severe manifestations and encephalopathy are not described from other parts of the country even in hospitalized patients, which makes us think that the differences are at least in part due to greater virulence and neurotropism of the serotypes circulating in this region. Dengue Bulletin Volume 32,

7 Only serological diagnosis by IgM ELISA was possible in our patients. IgM, however, has its limitations in the diagnosis of dengue infection. Studies have shown 80% positivity in the first 5 days of illness, 93% positivity between 6 and 10 days of illness onset, and 99% positivity after the 10 th day [1]. A negative IgM in a patient sampled early in the illness therefore does not totally rule out dengue infection. On the other hand, a positive IgM does not always mean that the current illness is dengue, but that dengue infection has occurred in the recent past, i.e days. IgM positivity therefore may merely mean that dengue transmission is going on. Further, although IgM-type antibodies are held to be specific between flaviviruses, some crossreactivity was still possible, especially with Japanese encephalitis, which is endemic here. Due to these limitations, WHO has put the diagnosis of dengue infection on the basis of positive acute phase IgM ELISA test as probable only. However, all our patients were clinically suspected as dengue, and, therefore, are very likely to have had dengue viral infection. In conclusion, clinical manifestations of dengue as seen by us in Lucknow over the last few years appear to be different from those seen in other parts of the country, or even in the same region in earlier epidemics. The manifestations also seem to be changing over this period. DF and DHF/DSS are not the only clinical presentations. Encephalopathy is an important presentation in hospitalized children. The spectrum of findings may be explained by the presence of different circulating serotypes in this region. It would be interesting to correlate serotype with clinical features in this infection. Our report, however, is based on only a small study and should be corroborated by a larger, detailed study. References [1] Gubler DJ. Dengue and dengue hemorrhagic fever. Division of Vector Borne Infectious Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, [2] Ramakrishanan SP, Gelfand HM, Bose PN, Sehgal PN, Mukharjee RN. The epidemic of acute haemorrhagic fever, Calcutta, 1963: epidemiological Inquiry. Indian J Med Res. 1964; 52: [3] Bharaj P, Chaher HS, Pandey A, Diddi K, Lalit D, Guleria R, Kabra SK, Broor S. Concurrent infections by all four dengue virus serotypes during an outbreak of dengue in 2006 in Delhi. India. Virol. J. 2008; 5: 1-4. [4] Tripathi P, Kumar R, Tripathi S, Tambe JJ, Venktesh V, Descriptive epidemiology of dengue transmission in Uttar Pradesh. Indian Paed. 2008, Apr, 45, pp [5] World Health Organization. Dengue haemorrhagic fever: diagnosis, treatment, prevention and control, 2 nd ed. Geneva, [6] Kumar R, Tripathi S, Tambe JJ, Arora V, Srivastava A, Nag VL. Dengue encephalopathy in children in northern India: Clinical features and comparision with nondengue. J. Neurol. Sci. 2008, Jun, 269(1-2): [7] Kumar R, Tripathi P, Tripathi S, Kanodia A, Venkatesh V. Prevalence of dengue infection in north Indian children with acute hepatic failure. Ann Hepatol. 2008; 7: [8] Kumar R, Tripathi P, Tripathi S, Kanodia A, Pant S, Venkatesh V. Prevalence and clinical differentiation of dengue fever in children in northern India. Infection. 2008; 16: [9] Agarwal R, Kapoor S, Nagar R, Misra A. A clinical study of the patients with dengue 124 Dengue Bulletin Volume 32, 2008

8 haemorrhagic fever during epidemic of 1996 at Lucknow, India. Southeast Asian J Trop. Med. Pub. Hlth. 1999; 30: [10] Kishore J, Singh J, Dhole TN, Ayyagari A. Clinical and serological study of first large epidemic of dengue in and around Lucknow, India. Dengue Bulletin. 2006; 30: [11] Aggarwal A, Chandra J, Aneja S, Patwari AK, Dutta AK. An epidemic of dengue hemorrhagic fever and dengue shock syndrome in children in Delhi. Indian Pediatr. 1998; 35: [12] Hendarto SK, Hadinegoro SR. Dengue encephalopathy. Acta Paediatrica Jpn. 1992; 34(3): [13] Cam BV, Fonsmark L, Hue NB, Phuong NT, Poulsen A, Heegaard ED. Prospective case control study of encephalopathy in children with dengue hemorrhagic fever. Am J Trop Med Hyg. 2001; 65: [14] Kankirawatana P, Chokephaibolkit K, Yoksan S, Pathavathana P. Dengue infection presenting with central nervous system manifestations. J Child Neurol. 2000; 15: [15] Thisyakorn U, Limpitikul W. Dengue infection with central nervous system manifestations. Southeast Asian J Trop Med Public Health. 1999; 30(3): [16] Panchareon C, Thisyakorn U. Neurological manifestations in dengue patients. Southeast Asian J Trop Med Public Health. 2001; 32(2): [17] Lum LC, Lam SK, Choy YS, George R, Harun F. Dengue encephalitis: a true entity? Am J Trop Med Hyg. 1996; 54(3): [18] Solomon T, Dung MN, Vaughn DW, Kneen R, Thao LTT, Boonyos R, Loan HT, Day NPJ, Farrar J, Myint KSA, Warrell M, James WS, Nisalak A, White NJ. Neurological manifestations of dengue infection. Lancet. 2000; 355: [19] Rategeri VH, Shepur TA, Wari PK, Chavan SC, Mujahid IB, Yergolkar PN. Clinical profile and outcome of dengue fever cases. Indian J Pediatr. 2005; 72: [20] Narayanan M, Aravind MA, Thilothammal N, Prema R, Sargunam CS, Ramamurty N. Dengue fever epidemic in Chennai a study of clinical profile and outcome. Indian Pediatr. 2002; 39: [21] Singh NP, Jhamb R, Agarwal SK, Guha M, Dewan R, Daga MK, Chakravarti A, Kumar S. The 2002 outbreak of dengue fever in Delhi, India. Southeast Asian J Trop Med Public Health. 2005; 36: [22] Faridi MM, Aggarwal A, Kumar M, Sarafrazul A. Clinical and biological profile of dengue hemorrhagic fever in children in Delhi. Trop Doct. 2008; 38: [23] Larreal Y, Valero N, Estevez J, Reyes I, Maldonado M, Espina LM, Arias J, Melean E, Anez G, Atencio R. Hepatic alterations in patients with dengue. Invest Clin.2005; 46(2): [24] Kou CH, Tai DI, Chang-Chien CS, Lan CK, Chiou SS, Liaw YF. Liver biochemical tests and dengue fever. Am J Trop Med Hyg. 1992; 47(3): [25] Nguyen TL, Nguyen TH, Tieu NT. The impact of dengue hemorrhagic fever on liver function. Res Virol. 1997; 48: 273. [26] Souza LJ, Alvez JG, Nogueira RM, Gicovate NC, Bastos Da, Siqueira EW, Souto Filho JT, Cezario T, Soares CE, Carneiro RC. Aminotransferase changes and acute hepatitis in patients with dengue fever: analysis of 1,585 cases. Braz J Infect Dis. 2004; 8(2): Dengue Bulletin Volume 32,